Cellular mechanisms of neurodegeneration

Dr Sarah Tabrizi is Professor of Clinical Neurology based in the Dept of Neurodegenerative Disease at the Institute of Neurology, University College London and also an Honorary Consultant Neurologist/Neurogeneticist at the National Hospital for Neurology and Neurosurgery at Queen Square in London. Her group focuses on studying cellular mechanisms of neurodegeneration in a variety of different systems from in vitro modelling to direct study of the human disease. Her main areas of research are in protein misfolding diseases, with focus on Huntington’s disease and prion biology.

Prion group research

My prion lab group works closely with John Collinge and colleagues in the MRC Prion Unit and is interested in the cell biology of prions. Prion diseases, such as BSE in cattle and variant CJD (vCJD) in humans, are rare but deadly diseases of the brain. In these diseases, normal prion protein in our cells becomes abnormally shaped and forms toxic prions. These prions start to accumulate in the brain, and cause previously healthy brain cells to die. However, the exact mechanism by which this abnormal prion protein kills cells is not known. Our work suggests that a problem with the ubiquitin-proteasome system (UPS) might be involved. The UPS is a type of cellular recycling machinery that breaks up damaged proteins into small units and helps dispose of them. This protects the cells from a potentially toxic build-up of faulty proteins inside the cell. My group is working on studying this cellular garbage disposal system in detail to help us understand how prions cause brain cells to die and how prions may be cleared in the cell. Some of our work was summarised in an article in The Economist www.economist.com/science and in a review article in the New England Journal of Medicine (AL. Goldberg. On prions, proteasomes and mad cows. New England Journal of Medicine 2007 Sept 13; 357 (11): 1150-1152).

Specifically, work in my prion group focuses on 3 main research areas:

Cellular mechanisms of prion-mediated neurodegeneration and interactions with the ubiquitin-proteasome system in vitro and in vivo

Clearance of prion protein and the role of the ubiquitin-proteasome system and autophagy

Cellular trafficking pathways of misfolded prion protein and the link between altered trafficking and neuronal toxicity

Neurodegenerative diseases are one of the biggest health problems in our ageing society, and uncovering basic molecular mechanisms is fundamental for the development of therapeutics. Many common neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease occur as a result of misfolding and aggregation of cellular proteins (protein conformational disorders).

Prion disease is the prototypical protein misfolding neurodegenerative disorder as its pathogenesis is associated with aberrant misfolding of a host cellular protein only (the protein-only hypothesis). Thus, advances in the understanding of prion pathophysiology have major implications for other neurodegenerative diseases through the elucidation of common cellular mechanisms.

This figure shows differentiated human neural stem cells (197VM cells, Reneuron Ltd). These are composed of >90% neurons. Neurons are stained with βIII-tubulin (green), glial cells with GFAP (red) and nucleii with Hoescht (blue). We are using these cells to try and model prion diseases in vitro.

Huntington’s disease (HD)

Understanding disease progression in Huntington’s disease

Huntington’s disease (HD) is a devastating inherited neurodegenerative disease that commonly affects people in mid-adulthood. Our understanding of the pathogenesis of HD has expanded dramatically in recent years and in animal models of HD, many interventions can slow progression clinically and pathologically. Neuronal death is preceded by dysfunction, which may be reversible by disease-modifying therapies, resulting in clinical improvement even after the onset of symptoms.

I lead a large research programme in Huntington’s disease, focusing on the search for biomarkers of disease progression to power therapeutic trials. Such biomarkers are relevant to the underlying disease pathogenesis, and therefore are likely to yield fundamental insights into HD biology. For further details on our HD work – see www.hdresearch.ucl.ac.uk – this website is written specifically for the layperson with a particular aim towards HD patients, carers and families.

Overview of our HD Inflammation work

In some of our recent work (Björkqvist et al., J Exp Medicine 2008), we showed widespread innate immune activation detectable throughout the disease course. This work represents a significant advance in our understanding of the role of the mutant Huntingtin gene and the pathogenesis of Huntington’s disease. It describes a novel pathogenic pathway quite distinct from the prevailing view that HD is caused solely by effects of mutant huntingtin within neuronal cells. For the first time, we demonstrated that the presence of the mutant gene in immune cells of myeloid lineage (monocytes, microglia and macrophages) was sufficient to cause these cells to behave abnormally, over-producing inflammatory cytokines when stimulated. We also identified the earliest detectable change yet reported in blood in HD patients, showing that interleukin-6 was significantly increased in a group of premanifest HD mutation carriers with a mean of 16 years to the development of symptoms. Our findings were replicated in three widely-used mouse models of HD, suggesting that inflammatory dysfunction may be a valuable translational research tool for HD therapeutics work. Overall this work suggests a key role for the innate immune system in the pathogenesis of HD and suggests important new avenues for research into biomarkers and disease-modifying therapies for HD. This work is continuing, and we are working on identifying the downstream signalling pathways whereby mutant huntingtin activates the innate immune system, by studying both cell-autonomous and non-cell autonomous mechanisms.

TRACK-HD

I am global PI for TRACK-HD - an observational trial in premanifest and early HD. This major international initiative aims to determine what combination of measures is most sensitive for detecting change over the natural course of premanifest and early Huntington’s disease, with a view to validating these as potential outcome measures for use in future therapeutic trials. The study will yield new insights into the neurobiology of premanifest HD in the years prior to overt disease onset. TRACK-HD is the first such study to use full electronic data capture and incorporates a range of novel imaging, biochemical and clinical assessment tools. For more information on TRACK-HD see www.track-hd.net.

Some of our recent research in HD has been the subject of articles in the Daily Telegraph, Daily Mirror, Reuters, Lancet Neurology and Scientific American (news articles).

Funding

Medical Research Council, High Q/CHDI (Cure-HD Initiative) Biomedical Research Foundation, the Wellcome Trust, UK Department of Health/NIHR and the UK Huntington’s Disease Association. I have academic-industrial research collaborations with Proteome Sciences, Reneuron Ltd and Novartis Ltd.